The present invention relates to 5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives, stereoisomers thereof, pharmacologically acceptable salts thereof and hydrates of them having a calcium channel-antagonistic effect and effective in treating and preventing intestinal diseases such as abnormal motor function of digestive tracts, particularly, irritable bowel syndrome, as well as pharmaceutical compositions containing them.
It is disclosed in, for example, European Patent No. 0404359A1 that 5,11-dihydrodibenzo[b,e][1,4]thiazepine derivatives are useful as calcium channel antagonists selectively effective on gastrointestinal tracts. In addition, Quinn P. et al and Wallis R. M. et al. also disclosed in Brit. J. Pharmacol. 1994, 112 (Suppl.), Abst 573P and Brit. Pharmacol. 1994, 112 (Suppl.) Abst 574P, respectively, that (S)-5-[1-(4-methoxyphenyl)ethyl]pyrrolidine-2-ylmethyl]-5,11-dihydrodibenzo[b,e][1,4]thiazepine maleate has the same effect as that described above. However, one of the defects of these compounds is that they have anticholinergic effect to cause side effects such as thirst and mydriasis.
As the social environment has become increasingly complicated, many people have been exposed to severe stress, and patients having irritable bowel syndrome mainly with irregular bowel movement and abdominal pain are increasing in number. Drugs given to the patients of such diseases include anticholinergics, laxatives, antidiarrheal drugs, intestinal drugs, mucosal paralyzing agents, drugs for controlling motor function of digestive tracts, autonomic drugs, Chinese orthodox medicines, antianxiety drugs, antidepressants, sleep promoting drugs and antipsychotic agents. However, the clinical effects of these drugs are yet insufficient and the drugs are not always satisfactory in view of their side effects. Under these circumstances, the development of a new-type drug having an excellent effect of improving the motor function of digestive tracts is demanded.
An object of the present invention is to provide new compounds having an excellent effect of improving the motor function of digestive tracts.
Another object of the present invention is to provide a pharmaceutical composition containing such new compounds.
Other objects of the present invention will be apparent from the following description and Examples given below.
It is generally considered that calcium channel antagonists are effective in treating intestinal diseases caused by abnormal acceleration of the contraction of intestinal tracts such as irritable bowel syndrome because they have a function of inhibiting the contraction of the smooth muscles. In fact, it was reported that calcium channel antagonists such as Nicardipine and Verapamil are effective on irritable bowel syndrome [Am. J. Gastroenterol., 80, 317 (1985); Gut. 28 1609 (1987); J. Clin. Psychiatry., 48, 388 (1987); an Pharmacol. Ther., 60, 121 (1993)]. However, these antagonists are rarely used clinically at present because of the main effects of the calcium channel antagonists on the cardiovascular system. Under these circumstances, the inventors made intensive investigations for the purpose of developing a calcium channel antagonist with low toxicity which is ineffective on the cardiovascular system but which is selectively effective on the intestinal tracts and is usable as a drug for abnormal motor function of intestinal tracts, particularly irritable bowel syndrome. After the investigations, the inventors have found that compounds represented by the following general formula [I-I] or [I-II] have calcium channel antagonistic activity selectively on the intestinal tracts and that they are usable as remedies for abnormal motor function of digestive tracts. The present invention has been completed on the basis of this finding.
Namely, the present invention relates to 5,11-dihydrodibenzo[b,e][1,4]oxazepine derivatives represented by the following general formula [I-I] or [I-II], stereoisomers thereof, pharmacologically acceptable salts thereof and hydrates of them; and pharmaceutical compositions containing them as active ingredients, particularly pharmaceutical compositions for treating or preventing abnormal motor function of intestinal tracts: 
wherein R1 through R5 may be the same or different from one another and they each represent a hydrogen atom, lower alkoxyl group, amino group or alkylamino group with the proviso that at least one of them represents the amino group or alkylamino group; R6 and R7 may be the same or different from one another and they each represent a hydrogen atom or hydroxyl group, or they together form xe2x95x90O; and Y1 represents a methylene group, sulfur atom or hydroxymethine group; 
wherein R11 through R15 may be the same or different from one another and they each represent a hydrogen atom, halogen atom, cyano group, hydroxyl group, lower alkoxyl group, amino group or alkylamino group, or R15 and R11, R11 and R12, R12 and R13 or R13 and R14 together form xe2x80x94O(CH2)nOxe2x80x94 group (n being 1, 2 or 3); Y2 represents a methylene group, sulfur atom or hydroxymethine group; A represents CH2, CHOH, CO or O, B represents CH2 or CHOH; or Axe2x80x94B represents CHxe2x95x90CH and D represents CH2, CH2xe2x80x94CH2 or CH2xe2x80x94CH2xe2x80x94CH2.
The lower alkoxyl groups represented by R1 through R5 in above general formula [I-I] are preferably those having 1 to 5 carbon atoms, and more preferably those having 1 to 3 carbon atoms. The alkylamino groups represented by R1 through R5 include monoalkylamino groups and dialkylamino groups. The alkyl groups are preferably those having 1 to 5 carbon atoms and more preferably those having 1 to 3 carbon atoms.
In the present invention, it is preferred that one of R1 through R5 is an amino group or alkylamino group, and the balance is hydrogen atom. Further, in this case, R6 and R7 are each hydrogen atom. Y1 is preferably methylene group.
R1 and R2 may be the same or different from each other and they each represent a hydrogen atom, amino group or alkylamino group in the present invention. It is preferred that R1 and R2 do not represent hydrogen atom at the same time and R3, R4 and R5 are each hydrogen atom. It is preferred in the present invention that both R1 and R2 represent an amino group or alkylamino group, and it is more preferred that one of R1 and R2 represents an amino group or alkylamino group and the other represents a hydrogen atom. It is also preferred that one of R1 and R2 represents an amino group or alkylamino group and the other represents a lower alkoxyl group. It is particularly preferred that R2 represents an amino group or alkylamino group, and R1 represents a hydrogen atom.
It is preferred in the present invention that R6 and R7 in general formula [I-I] each represent a hydrogen atom and Y1 represents methylene group. In these compounds, particularly preferred compounds are those represented by the following formulae, i.e. (R)-5,11-dihydro-5-[1-[2-(4-dimethylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, (R)-5,11-dihydro-5-[1-[2-(4-diethylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, (R)-5,11-dihydro-5-[1-[2-(3-dimethylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, (R)-5,11-dihydro-5-[1-[2-(3-methylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine and (R)-5,11-dihydro-5-[1-[2-(2-dimethylaminophenyl)ethyl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, as well as pharmaceutically acceptable salts thereof and hydrates of them. 
Compounds [I-I] of the present invention can be produced by, for example, following method A-1: 
wherein R1 through R7 and Y1 are as defined above, and X1 represents chlorine atom, bromine atom or iodine atom. It is preferred that R6 and R7 are each a hydrogen atom, and Y1 is methylene group.
Compounds [I-I] of the present invention can be produced by reacting a compound [II] with a halide represented by above general formula [III-I] in the presence of a base in a solvent.
The reaction solvents include amides such as N,N-dimethylformamide; ethers such as tetrahydrofuran, diethyl ether, dioxane and 1,2-dimethoxyethane; acetonitrile; toluene; xylene; benzene and dimethyl sulfoxide. The bases include lithium carbonate, sodium carbonate, potassium carbonate, sodium hydride, potassium hydride, lithium diisopropylamide, n-butyllithium, sodium methoxide and potassium t-butoxide.
The reaction temperature is in the range of usually 0 to 150xc2x0 C., preferably room temperature to 100xc2x0 C.
The reaction time, which varies depending on the reaction temperature and the variety of the solvent, is usually 1 to 150 hours.
The amount of each of compound [III-I] and the base is at least one mol, preferably 1 to 5 mols, per mol of compound [II].
Compound [II] used as a starting material in the above-described reaction can be produced by a well-known method [J. Med. Chem., 7, 609 (1964)].
The halides represented by above general formula [III-I] can be produced from proline, hydroxyproline, and thioproline obtained by reacting cysteine with formaldehyde, by a known method [EPO 404359A1].
In method A-1, the stereochemical structures of the compounds of the present invention were determined according to a reaction mechanism described in literatures [[EPO 404359A1 and Tetrahedron, 37, 2173 (1981)].
Compounds [I-I] of the present invention can also be produced by following method B-1: 
wherein R1 through R7 are as defined above, Y1 represents methylene group, sulfur atom or hydroxymethine group, V represents a group for protecting the amino group such as t-butoxycarbonyl group, benzyloxycarbonyl group or tosyl group, and W and Wxe2x80x2 each represent a leaving group such as chlorine atom, bromine atom, iodine atom, mesyl group or tosyl group.
Compounds [I-I] of the present invention can be produced by dropping, for example, an N-t-butoxycarbonyl-2-pyrrolidinylmethyl tosylate of above general formula [IV-I] into compound [II] to conduct the reaction in a solvent and thereby to form a compound of general formula [V-I], removing the protecting group to obtain a compound of general formula [VI-I] and reacting this compound with a compound of general formula [VII-I] in the presence of a base.
The base and the reaction solvent used in this process may be the same as those used in above-described reaction A-1.
A compound [I-I] of the present invention, wherein any of R1 through R5 is an amino group or monoalkylamino group, can be produced by synthesizing a precursor, wherein the amino group or monoalkylamino group is protected with an amino group-protecting group such as t-butoxycarbonyl group, benzyloxycarbonyl group, tosyl group, benzyl group or trityl group, or a corresponding nitro compound by method A-1 or B-1; and then removing the protecting group or reducing the nitro compound to obtain the amino group or monoalkylamino group. Alkylamino compounds or dialkylamino compounds can also be obtained by N-alkylating corresponding amino compounds or monoalkylamino compounds. 
wherein R represents a hydrogen atom or lower alkoxyl group, R6, R7 and Y1 are as defined above, R8 and R9 each represent a hydrogen atom or lower alkyl group, and Z represents an amino group-protecting group such as t-butoxycarbonyl group, benzyloxycarbonyl group, tosyl group, benzyl group or trityl group.
The protecting group is removed from compound [VIII] by an ordinary method to obtain compound [X] or compound [IX] is reduced by the catalytic hydrogenation or reduction with a metal to obtain compound [XI] which is then alkylated. Compounds [X] to [XII] are thus obtained. The alkylation can be easily conducted by using an ordinary alkylating agent such as an alkyl halide or alkyl tosylate, or by the reductive alkylation wherein the compound is condensed with a carbonyl compound and then the condensate is reduced. The dialkyl compounds can be obtained in two steps by producing compound [X] from compound [XI] and then converting the product into compound [XII]. When R8 and R9 are the same lower alkyl group, the compound can be directly converted into compound [XII] in one step.
In general formula [I-II], the halogen atoms of R11 through R15 include fluorine atom and chlorine atom; the lower alkoxyl groups include those having 1 to 5 carbon atoms such as methoxyl, ethoxyl and n-propoxyl groups; the alkylamino groups include monoalkylamino groups and dialkylamino groups; xe2x80x94O(CH2)nOxe2x80x94 groups include methylenedioxy, ethylenedioxy and propylenedioxy groups. In the halogen atoms, fluorine atom is preferred; and in the lower alkoxyl groups, those having 1 to 3 carbon atoms are preferred. In the monoalkylamino groups and dialkylamino groups, those wherein the alkyl group has 1 to 5 carbon atoms are preferred and those wherein the alkyl group has 1 to 3 carbon atoms are more preferred. Particularly preferred are dialkylamino-groups).
Axe2x80x94Bxe2x80x94D is preferably CHOHxe2x80x94CH2xe2x80x94CH2, CH2xe2x80x94CHOHxe2x80x94CH2, CHxe2x95x90CHxe2x80x94CH2, COxe2x80x94CH2xe2x80x94CH2, Oxe2x80x94CH2xe2x80x94CH2 or CH2xe2x80x94CH2xe2x80x94CH2.
In general formula [I], Y2is preferably methylene group, and R11 through R15 are not hydrogen atoms at the same time. R11 and R12 may be the same or different from each other and preferably, they each represent a hydrogen atom, halogen atom, cyano group, hydroxyl group, lower alkoxyl group, amino group or alkylamino group, R13 through R15 each represent a hydrogen atom, R11 and R12 together form xe2x80x94O(CH2)nOxe2x80x94 group (n being 1, 2 or 3). Preferably R11 represents hydrogen atom and R12 represents a halogen atom or lower alkoxyl group. More preferably, R12 represents a methoxyl group, and R11 and R13 through R15 each represent hydrogen atom, or R11 represents an amino group or alkylamino group, and R12 through R15 each represent hydrogen atom. In these compounds, particularly preferred compounds are (R)-5,11-dihydro-5-[1-[3-(4-methoxyphenyl)propane-1-yl]-2-pyrrolidinylmethyl]dibenzo[b,e][1,4]oxazepine, pharmacologically acceptable salts of them and hydrates of them: 
Compounds [I-II] of the present invention can be produced by, for example, following method A-2: 
wherein R11 through R15, A, B, D and Y2 are as defined above, and X2 represents chlorine atom, bromine atom or iodine atom.
Compounds [I-II] of the present invention can be produced by reacting compound [II] with a halide represented by above general formula [III-II] in the presence of a base in a solvent.
The same reaction solvent and base as those used for the above-described reaction A-1 can be used for this reaction.
The reaction temperature is in the range of usually 0 to 150xc2x0 C., preferably room temperature to 100xc2x0 C.
The reaction time, which varies depending on the reaction temperature and the variety of the solvent, is usually 1 to 150 hours.
The amount of each of compound [III-II] and the base is at lease one mol, preferably 1 to 5 mols, per mol of compound [II].
Compound [II] used as the starting material in the above-described reaction can be produced by a well-known method [J. Med. Chem., 7, 609 (1964)].
The halides represented by above general formula [III-II] can be produced from proline, hydroxyproline, and thioproline obtained by reacting cysteine with formaldehyde, by a known method [EPO 404359A1].
In method A-2, the stereochemical structures of the compounds of the present invention were determined according to a reaction mechanism described in literatures [[EPO 404359A1 and Tetrahedron, 37, 2173 (1981)].
Compounds [I-II] of the present invention can also be produced by following method B-2: 
wherein R11 through R15, A, B, D and Y2 are as defined above, V represents a group for protecting the amino group such as t-butoxycarbonyl group, benzyloxycarbonyl group or tosyl group, and W and Wxe2x80x2 each represent a leaving group such as chlorine atom, bromine atom, iodine atom, mesyl group or tosyl group.
Compounds [I-II] of the present invention can be produced by dropping, for example, an N-t-butoxycarbonyl-2-pyrrolidinylmethyl tosylate of above general formula [IV-II] into compound [II] to conduct the reaction in a solvent and thereby to form a compound of general formula [V-II], removing the protecting group to obtain a compound of general formula [VI-II] and reacting this compound with a compound of general formula [VII-II].
The reaction solvent used in this process may be the same as that used in above reaction method A-1.
Amino-substituted compounds can be produced by above-described method C.
The pharmacologically acceptable salts of compounds [I-I] and [I-II] of the present invention are mineral acid salts (inorganic acid salts) such as hydrochlorides, hydrobromides, sulfates and phosphates; and organic acid salts such as acetates, lactates, fumarates, maleates, malates, tartrates, citrates, oxalates, aspartates and methanesulfonates. Among them, the inorganic acid salts are preferred.
The compounds [I-I] and [I-II] of the present invention have one or more asymmetric carbon atoms and they can have optical isomers. The optical isomers, any mixtures of them and racemates are included in the compounds of the present invention. Among them, those wherein the configuration in 2-position of the pyrrolidine ring is in R-form are preferred. Since the compounds and pharmacologically acceptable salts thereof of the present invention can be in the form of their hydrates or solvated products, they are also included in the present invention.
When a compound of the present invention is used in the form of a pharmaceutical preparation or a pharmaceutical composition, it can be suitably mixed with pharmaceutical adjuvants such as a pharmaceutically acceptable excipient, carrier and diluent and orally or parenterally administered in the form of tablets, capsules, granules, fine granules, pills, syrup, suspension, emulsion, ointment, suppositories or injection prepared by an ordinary method. In the present invention, the medical preparation or medical composition comprising a compound of the present invention as the active ingredient and a pharmaceutically acceptable carrier and/or diluent is preferred. The carriers and diluents usable herein include glucose, sucrose, lactose, talc, silica, cellulose, methylcellulose, starch, gelatin, ethylene glycol, polyethylene glycol, glycerol, ethanol, water, oils and fats.
The dose and number of times of the administration of the compounds of the present invention can be suitably selected depending on the kind of the disease, and age and body weight of the patient. For example, in the oral administration of a compound of the present invention for treating intestinal diseases such as irritable bowel syndrome, the compound is given in an amount of about 0.1 to 1,000 mg/day all at once or in several portions a day.